5-methyl-3-isoxazole carboxylic acid hydrazides



n e .Sr ESPW O n S-METHYL-S-ISOXAZOLE CARBOXYLIC ACID No Drawing.Application April 15, 1958 Serial No. 728,544

8 Claims. 260-307) This invention relates to isoxazole derivatives. Moreparticularly, the invention relates to l-monoalkyland 1 monoaralkyl 2methyl 3 isoxazolylcarbonyl)- hydrazines, and to salts thereof.

The compounds of this invention may be represented by the followingstructural formula (I) I HCC--C0NH-NH-1oweralkylene-R orig-ti 0 whereinR represents hydrogen, hydroxy, phenyl, alkoxyphenyl, alkylphenyl andhalophenyl.

.The lower al-kylene group in Formula I refers to a straight chain orbranched chain saturatedhydrocarbon radical having a free bondavailable. at each chain end for attachment to the nitrogen atom and tothe substituent represented by R. T he al'koxyphenyl groups representedby R in Formula I above are preferably lower alkoxyplienyl groups suchas methoxyphenyl. .The alkylphenyl groups are preferably loweralkylphenyl groups such as methylphenyl, isopropylphenyl, etc.Halophenyl groups represented by R include, for example, chlorophenyl,bromophenyl, etc. The alkyl groups attached to the N -nitrogen of thehydrazide group resulting when R represents hydrogen are preferablylower alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl,n-amyl, isoamyL'etc. The analogous hydroxyalkyl groups when R representshydroxy, include, for example, hydroxylower alkyl groups such asZ-hydroxyethyl.

The compounds of this invention which are represente by Formula I abovemay be produced by initially reacting 5-methyl-3-isoxazole carboxylicacid hydrazide with an aldehyde or ketone, preferably in an inertorganic solvent such as ethanol, thereby producing an intermediaterepresented by the following'formula wherein R has the same significanceas above.

The compound having the Formula II above is then reduced, e.g.. withlithium aluminum hydride in ether or with sodiumor potassium borohydridein an aqueous alcohol, to produce the reduced compound of Formula I. Theproduct may then be separated by conventional procedures such asremoving .thespent reducing agent and solvent extracting, distilling,precipitating, etc. 1 The term flower alkylidene? used in Formula IIabove refers toastraight chain or branched chain hydrocarbonradiballhaving a dojuhle bond at one end of the chain for attachment; tothe nitrogen atom of the hydrazide group and a s'inglebond forattachment to thesubstituent represented by R, v

. Alternativelm angalkyl ester of, 5-methyl-3-isoxazole car boxylicfacid, e.g. ethyl .5-methyl-3-isoxazole carbox'ylate, may be, reacted inan inertsolv'ent with a monosubstituted hydrazine tciqntaining desiredsubstituent on the nitrogen atom to obtain the product represented byFormula I above. v

The products of this invention represented by Formula I above form acidadidtion salts with various inorganic and organic acids. Such salts arealso within the scope of this invention. Illustrative acid additionsalts include the hydrohalides, e.g. hydrochloride, hydrobromide,hydroiodide, other mineral acid salts, e.g. sulfate, phosphate, nitrateand other acid salts such as tartrate, citrate, camphorsulfonate,ethanesulfonate, salicylate, ascorbate, malate, mandelate, etc. Thehydrohalides, and in par-v ticular the hydrochloride, are preferred. Theacid addition salts are prepared by reacting the base with theappropriate acid, preferably in an inert solventwith an excess of theacid present, and recovering the product b conventional means from thereaction mixture.

The compounds of this invention are amine oxidase inhibitors, that is,they inhibit the activity of amine oxidase which effects thedeactivation of physiological regulators such as serotonin, tryptamine,epinephrine, etc., and stimulate the central nervous system. They areparticularly useful for relief of disturbed states in psychotherapy. Thebases having the Formula I, or pharmaceutically acceptable acid additionsalts thereof, may be administered orally or parenterally inconventional solid or liquid dosage forms, such as tablets, capsules,injectables, etc., comprising therapeutic doses incorporated inconventional solid or liquid vehicles either with orwithout excipients.

The following examples are illustrative of the invention. Alltemperatures are in degrees centigrade and melting points are corrected.I

7 Example 1 A 3-necked, l2-liter flask fitted with one high capacitycondensers, two dropping tunnels and an efiicient stirrer was set up insuch a manner that the reaction mixture could be cooled or heated. 25 g.of acetonylacetone, 88 ml. of concentrated nitric acid and 187 ml.'of-water was mixed and placed in the reaction flask. 325 g. ofacetonylacetone was placed in one dropping funnel and a mixture of 1144ml. of concentrated nitric acid with 2440' ml. of water was placed inthe second dropping funnel. Oxidation was initiated by heating thesolution in the flask. As soon as the initial reaction started tosubside, the reactants were added at a rate of approximately 8 ml. perminute of acetonylacetone and 80 ml. per minute of dilute nitric acid. i

After the final addition of the reactants, the mixture was cautiouslystirred for a few'minutes and the-flask was gently heated. The mixturewas refluxed for 30 minutes and cooled to 15. The colorless crystalswhich precipitated were filtered ofhwashed twice with 250 ml. portionsof ice water and dried at 60 over phosphorus pentoxide. The 5-methyl-3-isoxazole carboxylic acid sintered at 173 and melted at l-l76.

Example 2 710 g. of 5-methyl-3-isoxazole carboxylic acid, 7.1 liters ofethanol, and 825 ml. of 96% sulfuric acid was mixed while agitating. Thetemperature of the liquid rose to 4560. Stirring was continued for 15minutes and the solution was then permitted to stand for 24 hours. Theesterification solution was concentrated at 60 under vacuum to a volumeof 3.5 liters and poured into 10 liters of cracked ice. neutralized with1.8 liters of 28% ammonium hydroxide. The slightly alkaline solution wasthen extracted with ether in two portions of two liters each and thenwith ether in four portions of one liter each. v i

The six ether extracts were combined and concentrated under light vacuumto obtain crude ethyl 5-methyl-3- isoxazole carboxylate. The crude esterwas then-vacw Paitented oer. 13,1959

The solution wasthen drazine was dissolved in 15 ml. of ethanol.

amorphous solid.

3 um distilled at 13 to 14 mm. to obtain the pure ester, B.P. 115 117".

Example 3 733 g. of ethyl 5-methyl-3-isoxazole carboxylate was droppedin at room temperature into 875 g. of 85% hydrazine hydrate. Theinternal temperature rose to 4550. The solution was stirred for fourhours and then permitted to stand for 16 hours at 25. The mixture wasfiltered and the. mother liquor concentrated under vacuum to a solid.The combined yield of crude 5- methyl-3-isoxazole carboxylic acidhydrazide thus obtained was dissolved in 1.2 liters of hot ethanol. Oncooling, a white crystalline product melting at 142-143 separated.

Example 4 p 32 g. of ethyl 5-methyl-3-isoxazole carboxylate in 200 ml.of isopropanol was treated with 9 g. of methyl hydrazine. After stirringand warming to 60 for one hour, the excess material was removed invacuo. Upon addition of ethanol,1-methyl-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine crystallized, M.P.93-94.

Example 5 108 g. of acetaldehyde was added to 108 g. of S-methyl-3-isoxazole carboxylic acid hydrazide in one liter of ethanol. Thesolution became warm and was permitted to stand overnight. An additional50 g. of acetaldehyde was added to the solution and it was permitted tostand for 48 hours. On cooling, the product crystallized. The 1-ethylidene 2 (5 methyl 3 isoxazolylcarbonyl)hydrazine thus obtained wasrecrystallized from ethanol, M.P. 1-59160.

62 g. of 1-ethylidene-2-(5-methyl-3-isoxazolylcarbonyl) hydrazine wasslowly added as a dry powder over a period of two hours to g. of lithiumaluminum hydride in two liters of dry ether. The reaction mixture wasstirred for four hours and permitted to stand overnight at 25, Theexcess lithium aluminum hydride was decomposed with 150 ml. of ethylacetate and 100 ml. of water was then added to decompose the complex.The solid was separated by filtration and the ether layer wasconcentrated to an oil. 50 ml. of methanol was 4 100 g. of5-methyl-3-isoxazole carboxylic acid hydrazide in 500 ml. of ethanol.The solution became warm and was permitted to stand overnight. Thel-propylidene-Z- (5 methyl 3 isoxazolylcarbonyl)hydrazine which hadcrystallized was separated by filtration and recrystallized fromethanol, M.P. 137138. 86 g. ofl-propylidene-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine was reducedwith 18 g. of lithium aluminum hydride as described in Example 5. The1-propyl-2-(5-methyl-3- isoxazolylcarbonyl)hydrazine obtained wasrecrystallized from methanol, M.P. 48-5 0 v 0.5 g. of1-propyl-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine was dissolved in 15ml. of ethanol. To this solution was added 2 ml. of nitric acid. Uponthe addition of ether and cooling, 1-propyl-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine nitrate crystallized. The compound wasrecrystallized from ethanol-ether, M.P. 114-116.

Example 7 150 g'. of S-methyl-B-isoxazolyl carboxylic acid hydrazide in1500 ml. of acetone was heated for 30 minutes at 56. The solution wasevaporated to 500 ml. and cooled. The product,1-isopropy1idene-2-(5-methyl-3- isoxazolylcarbonyl)hydrazine separatedand was recrystaladded and the solution was decolorized with carbon.

The product then crystallized. The 1-ethyl-2-(5-methyl-3-iso'xazolylcarbonyl)hydrazine was recrystallized from methanol, M.P.80-81. V

0.5 g. of 1-ethyl-2-(5-methyl-3-isoxazlylcarbonyl)hydrazine wasdissolved in 15 ml. of ethanol. To this solution was added 2 ml. of asolution of hydrogen bromide in ethanol. Upon the addition of ether andcooling, l-ethyl-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine hydrobromidecrystallized. Upon recrystallization from ethanol-ether, thehydrobromide melted at 147-- 149".

0.5 g. of 1-ethyl-2-(5-methyl-3-isoxazolylcarbonyl)hy- 2 ml. ofphosphoric acid were added to the solution. Ether was then added and themixture was cooled. 1-ethyl-2-(5- methyl-3-isoxazolylcarbonyl)hydrazinephosphate seprated as a syrup which did not crystallize.

0.5 g. of 1-ethyl-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine wasdissolved in 15 ml. of ethanol. To this solution was added 2 g. oftartaric acid. Ether was added and the mixture was cooled.I-ethyI-Z-(S-methyl- 3-isoxazolylcarbonyl)hydrazine tartrateprecipitated as an amorphous solid.

. 0.5 g. of 1-ethyl-2-(5-methyl-3-isoxazolylcarbonyl)l1ydrazinewasdissolved in 15 ml. of ethanol. 2 g. of ascorbic acid was added to thissolution. Upon the addition of ether and cooling,1-ethyl-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine ascorbateprecipitated as an Example 6 100 g. of propionaldehyde was added to asolutionof lized from 500 ml. of acetone, M.P. 106-109.

16 g. of lithium aluminum hydride was dissolved in 2.5 kg. of dry ether.To this solution at 5 was added 72 g. of dry powderedl-isopropylidene-Z-(S-methyl-3- isoxazolylcarbonyl)hydrazine,portionwise, over a period of one to two hours. After the last of thesubstituted hydrazine had been added, the solution was stirred for twohours and then permitted to stand overnight. The excess lithium aluminumhydride was decomposed with 250 ml. of ethyl acetate and then 150 ml. ofwater were added to decompose the complex. After stirring for two hours,the mixture was refluxed for two hours, filtered and the solid filtercake was extracted with one liter of boiling benzene. The ether andbenzene solutions were combined and concentrated under vacuum to an oilwhich crystallized on cooling. The 1-isopropyl-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine was decolorized with activated carbon andrecrystallized twice from methanol, M.P. -87".

1 isopropyl-2(5-methyl-3-isoxazolylcarbonyl)hydrazine was also preparedby adding 543 g. of l-isopropylidene-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine over a period of one hour to 114 g. of sodium borohydride inthree liters of water at 25. The temperature rose to 55". After the lastof the substituted hydrazine was added, the suspension was stirred for/2 hour and ml. of acetic acid was added to destroy any excess sodiumborohydride. The suspension was cooled, filtered and the recovered solidwas recrystallized from methanol.

The procedure described in the preceding paragraph was repeated usingpotassium borohydride to obtain the same product.

Example 8 100 g. of 5-methyl-3-isoxazole carboxylic acid hydrazide wastreated with 100 g. of butyraldehyde in 500 ml. of ethanol. The solutionbecame hot and on cooling the product crystallized. The 1-butylidene-2-(5- methyl-3-isoxazolylcarbonyl)hydrazine was recrystallized fromethanol, M.P. 138l39.

98 g. of 1-butylidene-Z-(5-methyl-3-isoxazolylcarbonyl)hydrazine wasreduced with 18.5 g. of lithium aluminum hydride in ether according tothe procedure described in Example 5. A gel was obtained which wasextracted with benzene. The-benzene extract was concentrated to anamorphous residue comprising 1-butyl-2- (5-methyl-3isoxazolylcarbonyl)hydrazine. The latter was dissolved in ethanol andeth'anolic hydrogen chloride was added.1-buty1-2-(5-methyl-3-isoxazolylcarbonyl)- hydrazine hydrochlorideprecipitated and was recrystallized from ethanol, M.P. -'156.

t Example9 A To 70.5 g.=of'5imethyl-3-isoxazole carboxylic acidhydrazide and 600 ml. of ethanol was added 50 g. of nvaleraldehyde. Thecondensation product, l-n-amylidene- 2.(5-methyl-3-isoxazolylcarbonyl)hydrazine, was recovered by filtrationand recrystallized from ethanol, M.P. 114-115". 46g. of1-n-amylidene-2-(5-methyl-3- isoxazolylcarbonyl)hydrazine was reducedwith 8.5 g. of lithium aluminum hydride in ether. 7 The product wasrecovered as described in Example 5. The freebase, 1-namyl ,-2-(5-methyl-3-isoxazolylcarbonyl) hydrazine, was gummy and did notcrystallize. Upon addition of ethanolic hydrogen chloride, crystalline1-n-ampl-2-(5-methyl- 3-isoxazolylcarbonyl)hydrazine hydrochlorideseparated.

Upon recrystallization from ethanol, the colorless product melted at155-157.

. Example ethanol, the product melted at 185-186".

Example 11 800 g. of benzaldehyde was added to a hot solution (75) of 7liters of ethanol containing 720 g. of 5 -methyl- 3-isoxazole carboxylicacid hydrazide. The solution was stirred for ten minutes at which timethe product began to crystallize. On cooling at 4 for 14 hours, thesolid was filtered off under vacuum and the solid filter cake was washedtwice using 250 ml, of ice cold ethanol for each washing. The1-benzylidene-2-(5-methyl-3 isoxazolylcarbonyl)hydrazine wasrecrystallized from ethanol,

115 g. of 1-benzylidene-2-(5-methyl-3-isoxazolylcar bonyl)hydrazine wasadded portionwise over the period of an hour to 5 liters of anhydrousether containing 18.5

The reaction mixture g. of lithium aluminum hydride. was stirred forfour hours and permitted to stand overnight. The, excess lithiumaluminum hydride was decomposed with 250 ml. of ethyl acetate and 150ml. of water was added to decompose the complex. The solid was separatedby filtration and the ether layer was concentrated to about 500 ml. 200ml. of benzene was added to dehydrate the solution. Concentration wascontinued until a solid remained. The1-benzyl-2-(5-methyl-3-isoxazolylcarbonyDhydrazine was recrystallizedfrom methanol, M.P. 105l06.

1 benzyl-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine hydrochloride wasprepared by dissolving 4O of l benzyl 2(5-methyl-3-isoxazolylcarbonyl)hydrazine in 400 ml. of boiling ethanol.To the solution was added 15 ml. of 10 N hydrogen chloride gas inethanol. On cooling, 1 benzyl-2-(5-methyl-3-isoxazolylcarbonyl)hydrazinehydrochloride crystallized, M.P. 179-181.

0.5 g. of l-benzyl-2-(5-methyl-3-isoxazolylcarbonyl)- hydrazine wasdissolved in 15 ml. of ethanol. To this solution was added 2 g. ofoxalic acid. On addition of ether and cooling,1-benzyl-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine oxalatecrystallized. The oxalate was recrystallized from ethanol-ether, M.P.154-456.

0.5 g. of 1-benzyl-2-(S-methyl-3-isoxazolylcarbonyl)hydrazine wasdissolved in 15 ml. of ethanol. To this solu- 6 tion was added 2 ml. ofphosphoric acid. 011' addition of ether and cooling,-1-benzy1-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine phosphate separatedas a syrup which did not crystallize.

0.5 g. of 1-benzy1-2-(5-methyl-3-isoxazo1ylcarbonyl)hydrazine wasdissolved in 15 ml. of ethanol. 2 g. ascorbic acid was added to thissolution. On addition of ether and cooling,l-benzyl-2-(5-methyl-3-isoxazolylcarbonyl) hydrazine ascorbateprecipitated as an amorphous solid.

Example 12 394 g. (2.8 mols) of methyl-5-methyl-3-isoxazolecarboxylatewas placed in a 3-neck, round bottom flash fiteed with a stirrer andthermometer. 410 g. (3.35 mols, 20% excess) 'of .benzyl hydrazine wasadded; The mixture was heated to 60. Over a period of 25 minutes, in--termittent heat was applied, until a temperature of was attained. Thereaction solution was stirred for four hours during which timecrystallization took place. After standing overnight, the solid productwas dissolved in 1200 ml. of boiling methanol. The methanol solution wascooled to -10, filtered, and washed three times with 100 ml. portions ofcold methanol.

The crude 1-benzyl-2-(5-methyl 3-isoxazolylcarbonyl) hydrazine wasdissolved in 1500 ml. of .boiling ethanol. 400 ml. of 10 N hydrogenchloride in ethanol was added slowly with cooling and stirring. Theslurry was then diluted with 4 liters of ether and the suspension wasfiltered and washed three times with 200 ml. ether.

The hydrochloride salt thus formed was then sludged with three liters ofwater at 40 and 250 m1. of concentrated ammonium hydroxide was added.500 g. of crushed ice was introduced to cool the batch. It was thenfiltered, washed two times with 200 ml. of water and recrystallized from1500 ml. of methanol. The hot solution was filtered by gravity andcooled to -l5. The crystals were filtered, washed twotimes with 500 ml.of cold methanol and air dried overnight. The l-benzyl-Z-(5-methyl-3-isoxazolylcarbonyl)hydrazine melted at 107.

Example 13 To a solution of 1700 ml. of methanol, 300 ml. of water, and28 g. of 1-benzylidene-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine, wasadded over va period of fifteen minutes 28 g. of potassium borohydride(KBH The temperature rose to about 45-50. The solution was stirred forone hour during which time a precipitate formed as the reaction solutioncooled. After the reduction was completed, the excess KBH, was destroyedusing 75 ml. of acetic acid. The entire contents of the reaction wasevaporated to a solid and extracted by hot ether using 300 ml. for eachextraction for a total of three extractions. The residue was thenextracted with 200 ml. of boiling benzene. The ether extracts werecombined, concentrated to a solid and crystallized from methanol. Thecrude product thus obtained was purified by dissolving in 100 ml. ofethanol and adding 20 ml. 10 N hydrogen chloride in ethanol. On additionof 500 ml. of ether, l-benzyl-Z-(5-methyl-3-isoxazolylcarbonyl)hydrazinehydrochloride separated. The hydrochloride was recovered by filtrationand washed with 100 ml. of ether.

The hydrochloride was dissolved in 100 ml. of water at 60, filtered andcooled. 10 ml. of concentrated ammonium hydroxide were added and stirredfor ten minutes. The free base,1-benzyl-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine was recovered byfiltration and recrystallized from 50 ml. of methanol, M.P. 106-106.5.

Example 14 100 g. of anisaldehyde and 100 g. of 5-methyl-3-isoxazolecarboxylic acid in 800 ml. of ethanol was reacted as described inExample 5. The l-p-methoxybenzylidene-Z-(S-methyl-3-isoxazolylcarbonyl)hydrazine was recrystallized fromethanol, M.P. 187188.

130 g. of1-p-methoxybenzylidene-2-(5-methyl-3-isoxazolylc'arbonyDhydrazine wasreduced with 18 g. of lithium aluminum hydride as described in Example5. The l-(p-methoxybenzyl)-2-(5-methyl-3-isoxazolylcarbonyl)hydrazinewas recrystallized from methanol, M.P. 8889.

[T he free base obtained above was dissolved in ethanol and ethanolichydrogen chloride was added. Upon addition of ether,l-(p-methoxybenzyl)-2-(5-methyl-3-isoxazolylcarbonyl)hydrazinehydrochloride crystallized. Upon recrystallization from ethanol-etherthe product melted at l66l67 with dec.

Example 15 70.5 g. of -methyl-3-isoxazole carboxylic acid hydrazide in800 ml. of ethanol was treated with 71 g. of ochlorobenzaldehyde asdescribed in Example 5. The 1- (o-chlorobenzylidene) -2- 5-methyl-3-isoxazolylcarbonyl) hydrazine was crystallized from ethanol,M.P. 172-173".

158 g. ofl-(o-chlorobenzylidene)-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine wasreduced with 23 g. of lithium aluminum hydride in ether as described inExample 5. Thel-(o-chlorobenzyl)-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine wasrecrystallized from ethanol, M.P. 100-101".

Example 16 70 g. of 5-methyl-3-isoxazole carboxylic acid hydrazide wasreacted with 100 g. of phenyl acetaldehyde in 500 ml. of ethanol asdescribed in Example 5. Thel-phenethylidene-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine wasrecrystallized from ethanol, M.P. 157158.

83 g. of l-phenethylidene-Z-(S-methyl-B-isoxazolylcarbonyl)hydrazine wasreduced with 13 g. of lithium aluminum hydride and 5 liters of ether asdescribed in Example 5. The free base,l-phenethyl-Z-(5-methyl-3-isoxazolylcarbony1)hydrazine, was an amorphousproduct which did not crystallize. The free base was dissolved inethanol and ethanolic hydrogen chloride was added. On cooling,1-phenethyl-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine hydrochloridecrystallized. The hydrochloride was recrystallized from hot ethanol,M.P. 187189, with dec.

Example 17 A commercial sample of B-hydroxyethyl hydrazine, containingabout 80% of the named compound, was fractionated. 40 g. of therelatively pure, S-hydroxyethyl hydrazine recovered from the fractionboiling at 155- 160/ 30 mm. was heated at reflux with 78 g. of ethyl-5-methyl-3-isoxazole carboxylate and 100 ml. of isopropanol. Thesolution was concentrated to a small volume and ether was added. Onstanding at 4, a few crystals separated. These crystals were used toseed a solution of the oil residue in alcohol-ether. 1-(2-hydroxyethyl)-2-(5-methyl-3-isoxazolylcarbonyl)hydrazine crystallized. The product wasrecrystallized once from ethanol and twice from hot Water. It melted at119120.

Example 18 48 g. of 5-methyl-3-isoxazole carboxylic acid hydrazide wasreacted in 500 ml. of ethanol with 50 g. of p-isopropylbenzaldehyde at25 for 14 hours as described in Example 5. The recovered solid,l-(p-isopropylbenzylidene)-2-(S-methyl-3-isoxazolylcarbonyl)hydrazine,was

recrystallized from ethanol, MLP. 170-172.

g. of 1-(p-isopropylbenzylidene)-2(5-methyl-3-isoxazolylcarbonyl)hydrazine was reduced in 5 liters of anhydrous etherusing 9 g. of lithium aluminum hydride according to the proceduredescribed in Example 5. The recovered product,l-(p-isopropylbenzyl)-2-(5-methyl-3- isoxazolylcarbonyl)hydrazine wascrystallized from methanol, M.P. 107-108.

We claim:

1. A compound selected from the group consisting of bases represented bythe formula H(|J---G-C O-NH-lower alkylene-R OHa-O N wherein Rrepresents a member of the group consisting of hydrogen, hydroxy,phenyl, lower alkoxyphenyl, lower alkylphenyl and halophenylandpharmaceutically acceptable acid addition salts thereof.

2. A compound represented by the formula 8. 1-benzylidene-2-(5methyl-3-isoxazolylcarbonyl)hydrazine.

References Cited in the file of this patent UNITED STATES PATENTS HofferAug. 9, 1938 OTHER REFERENCES Cusmano: Chem. Abstracts, vol. 34, p. 7903(1940).

Speroni et al.: Chem. Abstracts, vol. 47, col. 11931 (1953).

Meltzer et al.: Chem. Abstracts, vol. 49, col. 1018 (1955).

IINITED STATES PATENT OFFICE; v CERTIFICATE 0F PatemNo. 2,908,688 vOctober 13, 1959 Thomas Samuel Gardner et al I It is hereby certifiedthat error appears in the printed specification of the above numberedpatent requiring correction and that the said Letters Patent should readas corrected below.

Column 2 line A, for adidtiofl read addition line 34, for "one" read metwo column 3, lines 59 and 60, for seprated" read separated column A,line 21, for isoicazolyl read as isoxazole column 5, line 13 for ampl"read me amyl w; column 6, line 6, for

2 g.a ascor read 2 g of ascor lines 1L, and 15, -for "flash fitee-d readme flask fitted column 8, line 14, claim 1, for that portion of theformula reading CO NH read me CO NH y line 43, after the word formulastrike out the period; lines 45 to 48, claim '7, left hand portion ofthe formula should appear as shown h'elow instead of as in the pateriSigned and sealed this 19th day of Agril lgo lo (smi) Attest;

KARL H ALLINE ROBERT C WATSON Attestihg Oificer Qorrmissioher of Patents

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BASES REPRESENTED BYTHE FORMULA